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  • In order to understand the determinants


    In order to understand the determinants of high affinity of with amide side chain, an X-ray crystal structure of human liver FBPase in complex with was determined (). The position of phosphonate group and tricyclic scaffold of is similar to those of with no side chain, which suggests the formation of the hydrophobic interaction as in the case of . In addition, the amide side chain of makes hydrogen bonds with the side chain of Asp178 and two water molecules, as expected. One water molecule interacts with the backbone carbonyl oxygen of Val160, the backbone nitrogen (NH) of Asp178 and the side chain of Asp178, and the other water molecule interacts with the backbone nitrogen (NH) of Cys179 and the side chain of Glu20. As a result, the side chain of forms the hydrogen bonding network involving Val160, Asp178, Cys179, Glu20, and two water molecules. This hydrogen bonding network would contribute to increase affinity. In summary, we further developed a series of tricyclic 8-indeno[1,2-][1,3]thiazoles as potent FBPase inhibitors with the aid of structure-based drug design. In order to enhance the metabolic stability, lead compound was modified to desamino compound which showed 10-fold increase in inhibitory activity relative to . The X-ray co-crystal structure of suggested that hydrophobic interaction would compensate for the loss of the hydrogen-bonding interactions through the amino group. Furthermore, introducing side chain with hydrogen bonding capability to led to the discovery of which exhibited over 10-fold increased activity compared to . This high affinity would be obtained by forming the hydrogen bonding network involving the side chain. The X-ray co-crystal structures of lead compounds (, ) provided us with the structural information which was beneficial to further developments, and these results demonstrated the usefulness of structure-based drug design. Further efforts on identifying various phosphonate prodrugs of the tricyclic 8-indeno[1,2-][1,3]thiazoles to investigate in vivo activity are underway. Acknowledgments
    Introduction As early as in 1927 of the last century Meyerhof (1927) reported on the synthesis of glycogen from lactate in a frog muscle. Shortly after Coris (Cori and Cori, 1929) postulated that lactate generated in muscle, as the result of the Pirfenidone glycolysis, is transported to the liver, where it is used for glucose synthesis in the process called gluconeogenesis, and then the synthesized glucose may be transported back to the muscle tissue (Cori cycle). Coris' postulate was like a dogma for nearly a half of a century. In the last decade of the twentieth century several papers appeared indicating that in the skeletal muscle of vertebrates up to 50% of lactate may be used in situ for the synthesis of glycogen (Gleeson, 1996). Lack of the glucose-6-phosphatase [E.C.] activity in the muscle cell precludes gluconeogenesis but the synthesis of glycogen is feasible. The synthesis of glycogen from carbohydrate precursors, like lactate, was called glyconeogenesis to distinguish this pathway from gluconeogenesis. The indispensable enzyme of gluconeogenesis as well as glyconeogenesis is fructose-1,6-bisphosphatase catalyzing the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate and orthophosphate. Since its discovery by Gomori (Gomori, 1943) the enzyme has been isolated, purified and characterized from a number of procaryotes and eucaryotes (yeast, plants, vertebrates and invertebrates). In vertebrate tissues, the muscle and liver FBPase isozymes have been found (Tillmann and Eschrich, 1998). The liver isozyme has been recognized as the regulatory enzyme of gluconeogenesis (Benkovic and deMaine, 1982, Tejwani, 1983), whereas we postulated that the muscle isozyme might be the regulatory enzyme of glyconeogenesis (Dzugaj, 2006). The basic kinetic properties of both isozymes are virtually identical, both require divalent cations like magnesium, manganese or zinc for their activity, both are activated by potassium ions, inhibited allosterically by AMP and competitively by Fru-2,6P2 (Van Schaftingen and Hers, 1981, Pilkis et al., 1981). The basic difference between the muscle and the liver isozymes concerns their sensitivity toward AMP. The muscle isozyme is 50 to 100 times more sensitive toward AMP than the liver isozyme. Recently we have found that the rabbit muscle FBPase is very sensitive to inhibition by calcium ions (Gizak et al., 2004). The determined I0.5 was in the range 0.6–0.8μM. On the contrary the liver isozyme is only slightly inhibited by calcium ions. We have also found that Glu69 is essential for the high affinity of the muscle isozyme toward calcium ions (Zarzycki et al., 2007). On the basis of the results of our investigation we postulated that calcium ions regulate glyconeogenesis in mammalian muscle tissue.